Background: Human papillomavirus (HPV) testing is more sensitive than cytology for detecting high-grade cervical intraepithelial neoplasia (CIN). We evaluated the performance of high-risk HPV (hrHPV) testing in routine screening. Methods: In all, 25 871 women (29–61) enrolled in our population-based cohort study were offered both cytology and hrHPV testing. High-risk HPV-positive women with normal cytology and an age-matched subcohort of hrHPV-negative women with normal cytology were invited for repeat testing after 1 and/or 2 years and were referred for colposcopy if they presented with abnormal cytology and/or a positive hrHPV test. The hrHPV-positive women with borderline or mild dyskaryosis (BMD) and all women with moderate dyskaryosis or worse (>BMD) were directly referred for colposcopy. Women with BMD and an hrHPV-negative test were advised to repeat cytology at 6 and 18 months and were referred for colposcopy if the repeat cytology test was abnormal. The main outcome measure was CIN grade 3 or worse (CIN3+). Results were adjusted for non-attendance at repeat testing. Results: The hrHPV-positive women with abnormal cytology had a CIN3+ risk of 42.2% (95% confidence interval (CI): 36.4–48.2), whereas the hrHPV-positive women with normal cytology had a much lower risk of 5.22% (95% CI: 3.72–7.91). In hrHPV-positive women with normal cytology, an additional cytology step after 1 year reduced the CIN3+ risk to only 1.6% (95% CI: 0.6–4.9) if the repeat test was normal. The CIN3+ risk in women with hrHPV-positive normal cytology was higher among women invited for the first time (29–33 years of age) (9.1%; 95% CI: 5.6–14.3) than among older women (3.0%; 95% CI: 1.5–5.5). Conclusion: Primary hrHPV screening with cytology triage in women aged ⩾30 years is an effective way to stratify women on CIN3+ risk and seems a feasible alternative to cytological screening. Repeat cytology after 1 year for hrHPV-positive women with normal cytology is however necessary before returning women to routine screening.

Aims: Cervical screening, currently performed by cervical cytology, depends on the timely detection of malignant lesions for its success. The presence of high-risk human papillomavirus (hrHPV) is associated with an increased risk of subsequent high-grade cervical intra-epithelial neoplasia (CIN2/3) and cervical cancer. The aim of this study was to determine the extent to which hrHPV is present in cervical smears with a high a priori chance of being false negative (ie, in normal smears preceding CIN2/3). Methods: Archival specimens of 187 women with CIN2/3 and preceding normal conventional smears were identified retrospectively. Of these specimens, 144 (77%) had adequate cytological samples for further HPV DNA testing. Results: Of 144 CIN2/3 lesions, preceding normal smears showed hrHPV positivity in 80% of cases. Of the hrHPV-positive smears, 69% were upgraded cytologically at rescreening compared with 24% of hrHPV-negative smears (p<0.001). Upgrading of smears was not associated with specific hrHPV types (p = 0.217). In over 90% of cases, type concordance in smear and CIN2/3 lesion was demonstrated. Conclusions: hrHPV is present in a high proportion of normal archival smears preceding CIN2/3, and false-negative cytology was highly associated with the presence of hrHPV. This supports the current notion that hrHPV testing can be used as a primary cervical screening tool. If so, hrHPV-positive cervical smears should be carefully examined for cytological abnormalities to reduce false-negative cervical cytology.

We assessed clearance rates of 14 high-risk human papillomavirus (hrHPV) types in hrHPV-positive women with normal cytology and borderline/mild dyskaryosis (BMD) in a population-based cervical screening cohort of 44 102 women. The 6-month hrHPV type-specific clearance rates, that is, clearance of the same type as detected at baseline, in women with normal and BMD smears were 43% (95% confidence interval (CI) 39–47) and 29% (95% CI 24–34), respectively. Corresponding 18-month clearance rates were markedly higher, namely 65% (95% CI 60–69) and 41% (95% CI 36–47), respectively. The lowest clearance rates in women with normal cytology were observed for HPV16, HPV18, HPV31, and HPV33. Significantly reduced 18-month clearance rates at a significance level of 1% were observed for HPV16 (49%, 95% CI 41–59) and HPV31 (50%, 95% CI 39–63) in women with normal cytology, and for HPV16 (19%, 95% CI 12–29) in women with BMD. Among women who did not clear hrHPV, women with HPV16 persistence displayed an increased detection rate of ⩾CIN3 (normal P<0.0001; BMD, P=0.005). The type-specific differences in clearance rates indicate the potential value of hrHPV genotyping in screening programs. Our data support close surveillance (i.e. referral directly, or within 6 months) of women with HPV16 and are inconclusive for surveillance of women with HPV18, HPV31, and HPV33. For the other hrHPV-positive women, it seems advisable to adopt a conservative management with a long waiting period, as hrHPV clearance is markedly higher after 18 months than after 6 months and the risk for ⩾CIN3 is low.

In one geographical area, 14 high-risk human papillomavirus types in cervical intraepithelial neoplasia (CIN2/3; n=139) and cervical squamous cell carcinoma (SCC; n=84) were analysed. HPV18 was more prevalent in SCC than CIN2/3 (OR 9.8; 95% confidence interval: 2.5–39). Other high-risk types prevalences corresponded in CIN2/3 and SCC. Evaluations using CIN2/3 as a measure of efficiency underestimate the contribution of HPV18 to SCC.

Background Tests for the DNA of high-risk types of human papillornavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented.Methods Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131.Findings 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (>= 6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0-001). The number of CIN3+ lesions over the two rounds did not differ between groups.Interpretation The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

Adding high-risk human papillomavirus (hrHPV) testing to screening increases the efficacy of cervical screening programmes. However, hrHPV testing may result in a lower participation rate because of the perceived association with sexually transmitted infections. We describe how testing for hrHPV was added to cervical screening in the POpulation-BAsed SCreening study AMsterdam (POBASCAM) trial. Participation rates of the screening programme before and after hrHPV implementation were evaluated in the region where the POBASCAM trial was carried out. The participation rate was 58.7% before and 61.4% after the addition of hrHPV testing to screening (p<0.001). An inventory of frequently asked questions is presented. Thus, hrHPV testing can be added to cervical screening by cytology without a decrease in participation rate.

We present the type-distribution of high-risk human papillomavirus (HPV) types in women with normal cytology (n=1467), adenocarcinoma in situ (ACIS) (n=61), adenocarcinoma (n=70), and squamous cell carcinoma (SCC) (n=83). Cervical adenocarcinoma and ACIS were significantly more frequently associated with HPV18 (OR(MH) 15.0; 95% CI 8.6-26.1 and 21.8; 95% CI 11.9-39.8, respectively) than normal cytology. Human papillomavirus16 was only associated with adenocarcinoma and ACIS after exclusion of HPV18-positive cases (OR(MH) 6.6; 95% CI 2.8-16.0 and 9.4; 95% CI 2.8-31.2, respectively). For SCC, HPV16 prevalence was elevated (OR(MH) 7.0; 95% CI 3.9-12.4) compared to cases with normal cytology, and HPV18 prevalence was only increased after exclusion of HPV16-positive cases (OR(MH) 4.3; 95% CI 1.6-11.6). These results suggest that HPV18 is mainly a risk factor for the development of adenocarcinoma whereas HPV16 is associated with both SCC and adenocarcinoma.

Cervical cancer is a preventable disease, occurring in relatively young women. In the Netherlands, population‐based cervical screening aims at women aged 30–60 years. We performed a population‐based study of the incidence of invasive cervical cancer in the Netherlands to evaluate trends, with emphasis on age at time of diagnosis. Histologic diagnosis was retrieved from the Netherlands Cancer Registry for all women residing in the Netherlands with invasive cervical cancer between January 1, 1989, and December 31, 1998. In this 10‐year period, the incidence rate of squamous cell carcinoma decreased significantly from 7.1/100,000 to 6.1/100,000 (p < 0.001), with the greatest decrease in women aged 60–74 (–5.5%). While the overall incidence rate of adenocarcinoma remained stable, it increased in women aged 15–29 (+15.8%) and in women aged 30–44 (+2.5%), though the number of cases was small. For squamous cell carcinoma, the incidence of stage II at diagnosis decreased most (–2.7%). There was no change in stage at diagnosis for adenocarcinoma. Most cases of cervical cancer, 60.5%, were detected between ages 30 and 60 years, i.e., the Dutch screening age interval. Cervical cancer in women below age 30 contributed 5.0% to the total incidence, with 3.0% occurring between ages 27 and 29. Thus, screening for cervical cancer in the Netherlands is associated with a decrease in the incidence of squamous cell carcinoma and adenocarcinoma incidence appears to be increasing in younger women. © 2004 Wiley‐Liss, Inc.

Aim: To describe the effect of introducing the CISOE-A framework for reporting cervical cytology results, including changes in repeat and referral advice in the Netherlands, on the efficacy of the screening programme. Changes in the distribution of cytological results, the detection rate of cervical intraepithelial neoplasia (CIN) lesions, and the detection rate of squamous cervical carcinoma are reported. Methods: The results of all gynaecology cytological and histological examinations, as registered in the nationwide database for histopathology and cytopathology (PALGA) from 1990 to 2000, were retrieved from seven laboratories in the greater Amsterdam area. Results: After the introduction of the CISOE-A classification, cytological results with equivocal diagnoses decreased significantly from 11.3% to 2.6%, without an increase in the percentages of moderate dyskaryosis or worse. During the study period, the detection rate of histologically diagnosed high grade CIN lesions increased significantly from 4.1 to 6.4/1000 smears, whereas there was no change in the detection rates of low grade lesions or invasive cervical cancer. Conclusions: The introduction of the new CISOE-A classification system resulted in a substantial decrease of equivocal results and repeat recommendations, without a decrease in the detection rate of high grade lesions, making the screening programme more efficacious.

To evaluate the effect of population-based cervical cancer screening on the occurrence of cervical cancer in The Netherlands, we investigated the incidence and survival of cervical cancer registered by a cancer registry in the Greater Amsterdam area. The incidence rate of squamous cell carcinoma decreased significantly from 9.2/100 000 women in 1988 to 5.9/100 000 in 2000 (P<0.001). The incidence rate of adenocarcinomas remained stable. After adjustment for age, stage and lymph node involvement, the relative risk of death was 1.6 times higher for patients with adenocarcinomas than for patients with squamous cell carcinoma (95% CI 1.2–2.1). The decreased survival was related to histological type, as the effect remained significant after correction for confounding factors. Over time, the prognosis of women with squamous cell carcinoma improved significantly. No significant change was observed for women diagnosed with adenocarcinoma. These results suggest that the screening programme in The Netherlands as executed in the Greater Amsterdam area is associated with a decreased incidence and increased survival of patients with squamous cell carcinoma, but fails to detect (pre)malignant lesions of adenocarcinoma. Since more than 92% of adenocarcinomas and its precursors contain high-risk HPV, adding HPV testing to cytologic screening might improve the present screening programme in detecting adenocarcinoma and its precursor lesions.